Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the invention relates to 2-heterocyclylalkyl-2-penem compounds of the formula wherein R1 is hydroxy or protected hydroxy, R2 is carboxyl or functionally modified carboxyl, R3 is a monocyclic heteroaryl radical bonded via a ring nitrogen atom with 1 to 4 ring nitrogen atoms and m is an integer from 3 to 12, salts of compounds of the formula I, Process for the preparation of compounds of formula I, pharmaceutical preparations containing such compounds and their use for the production of pharmaceutical preparations or as pharmacologically active compounds.
• Functionally modified carboxyl R2 is in particular cleavable esterified carboxyl or protected carboxyl R2 ⁇ under physiological conditions.
• Esterified carboxyl groups R2 which are cleavable (i.e. metabolizable) under physiological conditions are known from cephalosporin, penicillin and penem chemistry.
• Suitable groups are primarily acyloxymethoxycarbonyl groups, where acyl e.g. is the residue of an organic carboxylic acid, primarily an optionally substituted lower alkane carboxylic acid, or wherein acyloxymethyl forms the residue of a lactone.
• Such groups are e.g. Lower alkanoyloxymethoxycarbonyl, amino lower alkanoyloxymethoxycarbonyl, especially ⁇ -amino lower alkanoyloxymethoxycarbonyl, and 4-crotonolactonyl.
• a monocyclic heteroaryl radical R3 with 1 to 4 ring nitrogen atoms bonded via a ring nitrogen atom is in particular a corresponding 5-membered heteroaryl radical, ie a corresponding aza-, diaza-, triaza- or tetraza-cyclic radical of aromatic character.
• Corresponding heteroaryl radicals R3 are, for example, 1-pyrrolyl, 1-diazolyl, such as 1-imidazolyl or 1-pyrazolyl, 1,2,4- or 1,3,4-triazol-1-yl or 1- or 2-tetrazolyl.
• R3 radicals are unsubstituted or can, for example, by optionally etherified or esterified hydroxy, for example hydroxy, lower alkoxy, lower alkanoyloxy or halogen, optionally etherified mercapto, for example mercapto, lower alkylthio or phenylthio, lower alkyl, hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, carboxy-lower alkyl, carbynoyloxyalkyl, carbamoyloxyalkyl, carbamoyloxy, carbynoyloxyalkyl, carbamoyloxyalkyl, carbamoyloxyalkyl, carbamoyloxyalkyl, carbamoyloxyalkyl, carbamoyloxyalkyl, carbamoyloxyalkyl, carbamoyloxyalkyl, carbamoyloxyalkyl, carbamoyloxyalkyl, carbamoyl
• Lower alkanoyloxymethoxycarbonyl is e.g. Acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl.
• ⁇ -amino lower alkanoyloxymethoxycarbonyl is e.g. Glycyloxymethoxycarbonyl, valyloxymethoxycarbonyl or leucyloxymethoxycarbonyl.
• alkoxycarbonyloxy lower alkoxycarbonyl is e.g. Aethoxycarbonyloxymethoxycarbonyl or 1-Aethoxycarbonyloxyäthoxycarbonyl.
• alkoxy lower alkoxycarbonyl is e.g. Methoxymethoxycarbonyl or 1-methoxyethoxycarbonyl.
• a 2-oxo-1,3-dioxolen-4-ylmethoxy group which is optionally substituted in the 5-position of the dioxolen ring by lower alkyl or phenyl, is primarily a 5-phenyl and primarily a 5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxy group.
• Lower alkoxy is e.g. Methoxy, also ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobuyloxy or tert-butyloxy, and also n-pentyloxy, n-hexyloxy or n-heptyloxy.
• Lower alkanoyloxy is, for example, acetyloxy or propionyloxy.
• Halogen is e.g. Fluorine, chlorine, bromine or iodine.
• Lower alkylthio is e.g. Methylthio, ethylthio or n-propylthio.
• Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, furthermore n-pentyl, n-hexyl or n-heptyl.
• Hydroxy lower alkyl is e.g. Hydroxymethyl, 2-hydroxyethyl or 2,3-dihydroxypropyl.
• Lower alkanoyloxy lower alkyl is e.g. Acetoxymethyl or 2-acetoxyethyl.
• Carboxy lower alkyl is e.g. Carboxymethyl, 1-carboxy, 2-carboxy or 1,2-dicarboxyethyl.
• Carbamoyl lower alkyl is e.g. Carbamoylmethyl or 2-carbamoylethyl, while carbamoyloxy lower alkyl e.g. Is carbamoyloxymethyl or 2-carbamoyloxyethyl.
• Halogen lower alkyl is e.g. Chloromethyl, bromomethyl, 2-chloroethyl or 2,2-dichloroethyl.
• Amino lower alkyl is e.g. Aminomethyl or 2-aminoethyl
• lower alkylamino lower alkyl e.g. Methylaminomethyl, ethylaminomethyl, 2-methylaminoethyl or 2-ethylaminoethyl and di-lower alkylamino lower alkyl e.g. Is dimethylaminomethyl, 2-dimethylaminoethyl or 2-diethylaminoethyl.
• Lower alkanoylamino lower alkyl is, for example, acetaminomethyl, 2-acetaminoethyl or formylaminomethyl.
• Amino-carboxy-lower alkyl is e.g. 2-amino-2-carboxy-ethyl or 1-amino-1-carboxymethyl.
• Sulfone lower alkyl is e.g. Sulfomethyl or 2-sulfoethyl.
• Lower alkylamino is e.g. Methylamino, ethylamino, n-propylamino, isopropylamino or n-butylamino, while di-lower alkylamino e.g. Dimethylamino, diethylamino, di-n-propylamino or diisopropylamino means.
• Niederalkanoylamino is e.g. Acetylamino or propionylamino.
• Lower alkoxycarbonyl is e.g. Methoxycarbonyl or ethoxycarbonyl.
• Preferred esterified carboxyl groups R2 which are cleavable under physiological conditions are e.g. Lower alkanoyloxymethoxycarbonyl, e.g. Acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, and 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, e.g. 1-ethoxycarbonyloxyethoxycarbonyl.
• Preferred radicals R3 are e.g. unsubstituted or substituted by lower alkyl, such as methyl, 1-pyrrolyl, unsubstituted or substituted by lower alkyl, such as methyl, or halogen, such as chlorine, 1-pyrazolyl, unsubstituted or by lower alkyl, such as methyl, lower alkanoyloxy-lower alkyl, such as acetyloxymethyl, halogen-lower alkyl, such as chloromethyl Amino lower alkyl, such as aminomethyl or 2-aminoethyl, lower alkanoylamino lower alkyl, such as 2-acetylaminoethyl, and / or lower alkoxy, such as methoxy, substituted 1-imidazolyl, unsubstituted or substituted by lower alkyl, such as methyl, or lower alkoxycarbonyl, such as methoxycarbonyl or 1,3,4-triazol-1-yl, and
• m is an integer from 3 to 8.
• the functional groups present in the compounds of the formula I are optionally protected by protective groups which are used in penem, penicillin, cephalosporin and peptide chemistry .
• protective groups protect the functional groups in question from undesired condensation reactions, substitution reactions and the like during the synthesis of the compound of the formula I from its precursors.
• Such protecting groups are light, i.e. without unwanted side reactions taking place, for example solvolytic or reductive, can be split off.
• a hydroxyl group R 1 and also a hydroxyl group present in the R 3 group can be protected, for example by acyl radicals.
• Suitable acyl radicals are, for example, lower alkanoyl optionally substituted by halogen, for example acetyl, dichloroacetyl or trifluoroacetyl, benzoyl optionally substituted by nitro, for example benzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl, optionally lower alkoxycarbonyl substituted by halogen, for example 2-bromoethoxycarbonyl or 2,2 , 2-trichloroethoxycarbonyl, lower alkenyloxycarbonyl, for example allyloxycarbonyl, lower alkenyloxyoxalyl, for example allyloxyoxalyl, or phenyl-lower alkoxycarbonyl optionally substituted by nitro, for example benzyl oxycarbonyl or 4-
• hydroxy protecting groups are, for example, trisubstituted silyl, such as tri-lower alkylsilyl, for example trimethylsilyl, dimethyl- (2,3-dimethylbutyl) silyl or tert-butyl-dimethylsilyl, and 2-oxa- or 2-thiacycloalkyl with 5 to 7 carbon atoms, for example 2- Tetrahydropyranyl or 2-tetrahydrofuranyl.
• Preferred hydroxy protective groups are tri-lower alkylsilyl, lower alkenyloxyoxalyl and lower alkenyloxycarbonyl.
• a carboxyl group R2, and also a carboxyl group present in the rest R3, is usually protected in esterified form, the ester group being used under mild conditions, e.g. is easily cleavable under gently reductive, such as hydrogenolytic, or gently solvolytic, such as acidolytic or in particular basic or neutral hydrolytic conditions.
• esterified carboxyl groups contain as esterifying groups primarily lower alkyl groups which are branched in the 1-position or suitably substituted in the 1- or 2-position.
• Suitable carboxyl groups present in esterified form are, inter alia, benzyloxycarbonyl optionally substituted by nitro or lower alkoxy, such as methoxy, for example 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, lower alkanoylmethoxycarbonyl, such as acetonyloxycarbonyl, benzoylmethoxycarbonyl, in which the benzoyl group is preferably, if appropriate, for example by halogen, is substituted, for example phenacyloxycarbonyl, halogen-lower alkoxycarbonyl, such as 2-halogen-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl or 2-bromoethoxycarbonyl, lower alkenyloxycarbonyl, for example
• Preferred protected carboxyl groups R2 ⁇ are the 4-nitrobenzyloxycarbonyl, Lower alkenyloxycarbonyl, in particular allyloxycarbonyl, and the ethoxycarbonyl group substituted in the 2-position by tri-lower alkylsilyl, for example trimethylsilyl or di-n-butylmethylsilyl.
• a protected amino group in the radical R3 can be present, for example, in the form of an easily cleavable acylamino group or as an azido group.
• acyl is, for example, the acyl residue of an organic acid with e.g. up to 12 carbon atoms, especially one optionally e.g. by halogen or phenyl, substituted lower alkane carboxylic acid or in particular a carbonic acid half ester.
• Such acyl groups are, for example, halogeno lower alkanoyl, such as 2-haloacetyl, in particular 2,2,2-trifluoro or 2,2,2-trichloroacetyl, lower alkenyloxycarbonyl, e.g. Allyloxycarbonyl, optionally substituted in the 1- or 2-position lower alkoxycarbonyl, such as lower alkoxycarbonyl, e.g. tert-butoxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, halo-lower alkoxycarbonyl, e.g.
• halogeno lower alkanoyl such as 2-haloacetyl, in particular 2,2,2-trifluoro or 2,2,2-trichloroacetyl
• lower alkenyloxycarbonyl e.g. Allyloxycarbonyl, optionally substituted in the 1- or 2-position lower alkoxycarbonyl, such as lower al
• Preferred protected amino groups are azido, lower alkenyloxycarbonylamino, e.g. Allyloxycarbonylamino, and optionally nitro-substituted benzyloxycarbonylamino.
• Salts of compounds according to the invention are primarily pharmaceutically acceptable, non-toxic salts of compounds of the formula I.
• Such salts are formed, for example, from the acidic groups present in compounds of the formula I, for example carboxyl groups, and are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, for example sodium, potassium, magnesium or calcium salts, and also ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, for example triethylamine, hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tris- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, for example 4-aminobenzoic acid-2-di ethylaminoethyl ester, lower alkylene amines, for example 1-ethyl-piperidine, cycloalkylamines, for example dicyclohe
• Compounds of the formula I with a basic group can be acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acid, for example acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, oxalic acid Form citric acid, benzoic acid, mandelic acid, malic acid, ascorbic acid, methanesulfonic acid or 4-toluenesulfonic acid.
• Compounds of the formula I with an acidic and with a basic group can also be present in the form of internal salts, ie in zwitterionic form.
• the compounds of formula I have valuable pharmacological properties or can be used as intermediates for the preparation of such compounds with valuable pharmacological properties.
• Compounds of formula I, wherein R1 is hydroxy, R2 is carboxyl or an esterified carboxyl group cleavable under physiological conditions, R3 and m have the meanings given under formula I, and pharmacologically acceptable salts of such compounds with salt-forming groups have antibacterial effects. For example, they are effective in vitro against gram-positive and gram-negative cocci, e.g.
• Staphylococcus aureus Streptococcus pyogenes , Streptococcus pneumoniae , Streptococcus faecalis , Neisseria meningitidis and Neisseria gonorrhoeae in minimal concentrations of approx. 0.01 to 4 ⁇ g / ml.
• values of approx. 1 to approx. 20 mg / kg result with subcutaneous or oral administration.
• the compounds according to the invention are also effective against gram-negative rod-shaped bacteria, for example Haemophilus influenzae , Escherichia coli and Proteus spec., and anaerobes, for example Bacteroides spec., in vitro, for example, in minimal concentrations of approx 0.02 to approx. 32 ⁇ g / ml.
• the compounds of the present invention when tested with the enzyme dehydropeptidase isolated from human kidneys, prove to be remarkably stable and have half-lives of approximately 1.8 to approximately 4 hours.
• All compounds according to the invention have significantly lower MIC values (factor 4-20) compared to the comparative compound 1 *.
• the compounds of the present invention with approximately the same or better antibacterial activity against gram-positive and negative cocci, have a considerably greater stability towards the deactivating kidney enzyme dehydropeptidase and thus have a longer residence time and antibacterial activity in vivo .
• Their spectrum of activity is essentially limited to gram-positive and gram-negative cocci, with a particular high activity against the known problem germ Streptococcus faecalis is to be mentioned, while the effect against gram-negative rod bacteria is little or nonexistent.
• penems mentioned particularly suitable for the conical treatment of severe Staphylococcus and Streptococcus infections, in particular in cases in which the treatment with conventional broad-spectrum antibiotics does not appear to be promising, for example due to insufficient activity against resistant strains or is not indicated, For example, if the rest of the body's own flora (e.g. intestinal flora) should or must be protected. Because of their good tolerability and lower toxicity, the penems mentioned can also be used in particularly critical cases in which the administration of similarly specific antibiotics, such as vancomycin or lincomycin, cannot be accounted for due to excessive toxicity, for example in the case of impaired kidney function.
• similarly specific antibiotics such as vancomycin or lincomycin
• the new compounds can accordingly be administered as oral or parenteral antibacterial antibiotics, e.g. in the form of corresponding pharmaceutical preparations for the treatment of infections, in particular those caused by gram-positive or gram-negative cocci.
• the invention particularly relates to compounds of the formula I in which R1 is hydroxy or protected hydroxy, R2 is carboxyl, esterified carboxyl or protected carboxyl which is cleavable under physiological conditions, R3 is a monocyclic 5-membered heteroaryl radical having 1 to 4 ring nitrogen atoms which is bonded via a ring nitrogen atom unsubstituted or by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, mercapto, lower alkylthio, phenylthio, lower alkyl, hydroxy lower alkyl, lower alkanoyloxy lower alkyl, carboxy lower alkyl, carbamoyl lower alkyl, carbamoyloxy lower alkyl, halogen lower alkyl, amino lower alkyl, lower alkyl amino lower alkyl, di lower alkyl amino lower alkyl, lower alkanoylamino lower alkyl, amino carboxy lower alkyl, sulfone lower alkyl
• the invention relates mainly to compounds of formula I, wherein R1 is hydroxy, R2 is carboxyl or esterified carboxyl which is cleavable under physiological conditions, R3 is unsubstituted or substituted by lower alkyl, 1-pyrrolyl, unsubstituted or substituted by lower alkyl or halogen, 1-pyrazolyl, unsubstituted or by lower alkyl , Lower alkanoyloxy lower alkyl, halogen lower alkyl, amino lower alkyl, lower alkanoylamino lower alkyl and / or lower alkoxy substituted 1-imidazolyl, unsubstituted or substituted by lower alkyl or lower alkoxycarbonyl 1,2,4- or 1,3,4-triazol-1-yl, or unsubstituted or substituted by lower alkyl 1 - or 2-tetrazolyl and m is an integer from 3 to 10, and salts of compounds of formula I.
• the invention relates primarily to compounds of the formula I in which R1 is hydroxy, R2 is carboxyl or esterified carboxyl which is cleavable under physiological conditions, R3 is 1-tetrazolyl and m is an integer from 3 to 8, and salts of compounds of the formula I. .
• the invention relates primarily to the compounds of the formula I mentioned in the examples and their salts, in particular their pharmaceutically acceptable salts.
• the compounds of the present invention can be prepared by methods known per se.
• the new compound is prepared, for example, by using a ylide compound of the formula wherein R1, m and R3 have the meanings given by formula I, R2 ⁇ represents a protected carboxyl group, Z represents oxygen or sulfur and X ⁇ represents either a triple-substituted phosphono group or a double-esterified phosphono group together with a cation, ring-closing, or a compound of formula wherein R1, m and R3 have the meanings given by formula I and R2 ⁇ und Z have the meanings given by formula II, treated with an organic compound of trivalent phosphorus, and, if desired or necessary, protected functional groups in an available compound of formula I in the free transferred functional groups, and / or, if desired, in an available compound of formula I, a free carboxyl group R2 in a cleavable esterified carboxyl group under physiological conditions, and / or, if desired, in an available compound of formula I a radical R3 in converting another R3 group and
• the group X ⁇ in the starting material of the formula II is one of the phosphonio or phosphono groups customary in Wittig condensation reactions, in particular a triaryl, for example triphenyl, or tri-lower alkyl, for example tri-n-butylphosphonio group, or one by lower alkyl, for example ethyl, doubly esterified phosphono group, the symbol X ⁇ for the case of the phosphono group additionally comprising the cation of a strong base, in particular a suitable metal such as alkali metal ion, for example the lithium, sodium or potassium ion.
• Preferred as group X ⁇ are triphenylphosphonio on the one hand and diethylphosphono on the other hand together with an alkali metal ion, for example the sodium ion.
• the ring closure can occur spontaneously, i.e. in the manufacture of the starting materials, or by heating, e.g. in a temperature range from about 30 ° C to 160 ° C, preferably from about 50 ° C to about 110 ° C.
• the reaction is preferably carried out in a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. Cyclohexane, benzene or toluene, a halogenated hydrocarbon, e.g. Methylene chloride, an ether, e.g. Diethyl ether, a cyclic ether, e.g.
• Dioxane or tetrahydrofuran a carboxylic acid amide, a lower alkyl sulfoxide, or a lower alkanol or in a mixture thereof and, if necessary, in an inert gas, e.g. Nitrogen atmosphere.
• an inert gas e.g. Nitrogen atmosphere.
• An organic compound of trivalent phosphorus is derived, for example, from phosphorous acid and is in particular an ester thereof with a lower alkanol, for example methanol or ethanol, and / or an optionally substituted aromatic hydroxy compound, for example phenol or catechol, or an amide ester thereof of the formula P (OR a ) 2N (R b ) 2, in which R a and R b independently of one another are lower alkyl, for example methyl, or aryl, for example phenyl.
• Preferred compounds of trivalent phosphorus are tri-lower alkyl phosphites, for example trimethyl phosphite or triethyl phosphite.
• the reaction is preferably carried out in an inert solvent such as an aromatic hydrocarbon, e.g. Benzene or toluene, an ether, e.g. Dioxane or tetrahydrofuran, or a halogenated hydrocarbon, e.g. Methylene chloride or chloroform, at a temperature of about 20 ° to 140 ° C, preferably from about 20 ° to about 110 ° C, wherein 1 mol equivalent of a compound of formula III is reacted with at least 2 mol equivalents of the phosphorus compound.
• the compound of the formula III is preferably initially introduced into an inert solvent and the phosphorus compound, preferably dissolved in the same inert solvent, is added dropwise.
• the starting material of the formula III is prepared as indicated below and is reacted with the organic compound of the trivalent phosphorus without isolation from the reaction mixture, the end products of the formula I being formed.
• these, for example protected carboxyl, hydroxyl and / or amino groups can be prepared in a manner known per se by means of solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or by means of Reduction, in particular hydrogenolysis or chemical reduction, may be released gradually or simultaneously.
• the protected carboxyl group can be released in a manner known per se.
• ethoxycarbonyl substituted by a trisubstituted silyl group can be converted into free carboxyl in the 2-position by treatment with a carboxylic acid such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole.
• Optionally substituted benzyloxycarbonyl can be cleaved, for example, by means of hydrogenolysis, ie by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst.
• suitable substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl
• suitable substituted benzyloxycarbonyl can also be obtained by means of chemical reduction, for example by treatment with an alkali metal, for example sodium dithionite, or with a reducing metal, for example tin, usually in the presence of a hydrogen-donating agent which together with the Metal nascent hydrogen is capable of converting, such as a suitable carboxylic acid, for example a lower alkane carboxylic acid optionally substituted, for example by hydroxy, for example acetic acid, or an alcohol or thiol, preferably with water being added, into free carboxyl.
• a suitable carboxylic acid for example a lower alkane carboxylic acid optionally substituted, for
• An allyl protective group can be split off, for example, by reaction with a palladium compound, for example tetrakis (triphenylphosphine) palladium, optionally in the presence of triphenylphosphine and with the addition of an allyl group acceptor, such as a carboxylic acid, for example 2-ethylhexanoic acid, or a salt thereof or tributyltin hydride or Dimedon.
• a palladium compound for example tetrakis (triphenylphosphine) palladium
• triphenylphosphine triphenylphosphine
• an allyl group acceptor such as a carboxylic acid, for example 2-ethylhexanoic acid, or a salt thereof or tributyltin hydride or Dimedon.
• 2-halo-lower alkoxycarbonyl (optionally after conversion of a 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl group) or benzoylmethoxycarbonyl can also be converted into free carboxyl, benzoylmethoxycarbonyl also by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide, can be cleaved.
• a nucleophilic, preferably salt-forming reagent such as sodium thiophenolate or sodium iodide
• Substituted 2-silylethoxycarbonyl can also be treated with a the fluoride anion-providing salt of hydrofluoric acid, such as an alkali metal fluoride, for example sodium fluoride, in the presence of a macrocyclic polyether ("crown ether") or with a fluoride of an organic quaternary base, such as tetraniederalkylammonium fluoride, for example tetrabutylammonium fluoride, can be converted into free carboxyl.
• a the fluoride anion-providing salt of hydrofluoric acid such as an alkali metal fluoride, for example sodium fluoride
• a macrocyclic polyether such as tetraniederalkylammonium fluoride, for example tetrabutylammonium fluoride
• a lower alkoxycarbonyl group substituted in the 2-position by lower alkylsulfonyl or cyano can be converted into free carboxyl, for example by treatment with a basic agent, such as an alkali metal or alkaline earth metal hydroxide or carbonate, for example sodium or potassium hydroxide or sodium or potassium carbonate.
• a basic agent such as an alkali metal or alkaline earth metal hydroxide or carbonate, for example sodium or potassium hydroxide or sodium or potassium carbonate.
• esters can e.g. by reacting an optionally in situ salt of the acid with a reactive ester of a corresponding alcohol and a strong inorganic acid such as sulfuric acid or a strong organic sulfonic acid such as 4-toluenesulfonic acid.
• the carboxyl protecting group can be split off as described above and a resulting compound of the formula I with a free carboxyl group or a salt thereof by reacting with the reactive ester of a corresponding alcohol in a Transfer compound of formula I, wherein R2 is an esterifiable carboxyl group cleavable under physiological conditions.
• the protected hydroxyl group can be converted into the free hydroxyl group in a manner known per se.
• a hydroxy group protected by a suitable acyl group or an organic silyl group is released, such as a correspondingly protected amino group (see below);
• a tri-lower alkylsilyl group can, for example, also be cleaved with tetrabutylammonium fluoride and acetic acid (under these conditions, carboxy groups protected by trisubstituted silylethoxy are not cleaved).
• a compound of the formula I obtainable according to the invention with a protected amino group, this can be converted into the free amino group in a manner known per se, for example depending on the type of protective group, preferably by means of solvolysis or reduction.
• 2-halo-lower alkoxycarbonylamino (optionally after converting a 2-bromo-lower alkoxycarbonylamino group to a 2-iodo-lower alkoxycarbonylamino group) and 4-nitrobenzyloxycarbonylamino can be treated with a suitable chemical reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid or catalytically with hydrogen in the presence Palladium catalyst or be cleaved by treatment with an alkali metal, for example sodium dithionite.
• a suitable chemical reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid or catalytically with hydrogen in the presence Palladium catalyst or be
• Optionally substituted benzyloxycarbonylamino can, for example, by means of hydrogenoylysis, ie by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, and allyloxycarbonylamino by reaction with a compound of palladium, for example tetrakis (triphenylphosphine) palladium, optionally in the presence of triphenylphosphine groups and in the presence of an allyl acceptor , such as a carboxylic acid, for example 2-ethylhexanoic acid, or a salt thereof or tributyltin hydride or Dimeon.
• a suitable hydrogenation catalyst such as a palladium catalyst
• allyloxycarbonylamino by reaction with a compound of palladium, for example tetrakis (triphenylphosphine) palladium, optionally in the presence of triphenylphosphine groups and in the presence of an allyl accept
• An amino group protected by 2-halogeno lower alkanoyl for example 2-chloroacetyl
• 2-chloroacetyl can be released by treatment with thiourea in the presence of a base or with a salt, such as an alkali metal salt, of the thiourea and subsequent solvolysis such as alcoholysis or hydrolysis of the condensation product formed.
• An amino group protected by 2-substituted silylethoxycarbonyl can be treated with a fluoride anion-donating salt of hydrofluoric acid, such as an alkali metal fluoride, for example sodium fluoride, in the presence of a macrocyclic polyether ("crown ether") or with a fluoride of an organic quaternary base, such as tetraniederalkylammonium fluoride, for example tetraethylammonium fluoride, can be converted into the free amino group.
• a fluoride anion-donating salt of hydrofluoric acid such as an alkali metal fluoride, for example sodium fluoride
• a macrocyclic polyether such as tetraniederalkylammonium fluoride, for example tetraethylammonium fluoride
• An amino group protected in the form of an azido group is converted, for example, by reduction into free amino, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide or palladium, or by treatment with zinc in the presence of an acid such as acetic acid.
• a hydrogenation catalyst such as platinum oxide or palladium
• this carboxyl group can be converted into a functionally modified carboxyl group, such as an esterified carboxyl group, by processes known per se.
• a compound of formula I in which R3 is substituted by carboxyl with a lower alkanol a compound of formula I in which R3 is substituted by lower alkoxycarbonyl is obtained, preferably in the presence of a suitable condensing agent, e.g. a carbodiimide, works or the water formed is removed by azeotropic distillation.
• a suitable condensing agent e.g. a carbodiimide
• carboxyl groups on radicals R3 can also be used in reactive functional derivatives, such as mixed anhydrides, e.g. Transfer acid halides, or activated esters, and react them with an alcohol, e.g. convert a lower alkanol into correspondingly esterified carboxyl groups, the use of mixed anhydrides preferably in the presence of an acid-binding agent, such as an aromatic or tertiary aliphatic amine or an alkali metal or alkaline earth metal carbonate.
• mixed anhydrides e.g. Transfer acid halides, or activated esters
• an alcohol e.g. convert a lower alkanol into correspondingly esterified carboxyl groups
• an acid-binding agent such as an aromatic or tertiary aliphatic amine or an alkali metal or alkaline earth metal carbonate.
• the amino group can be converted into a substituted amino group, for example a lower alkylamino, di-lower alkylamino or lower alkanoylamino group.
• the conversion into a lower alkylamino or di-lower alkylamino group takes place, for example by reaction with a reactive esterified lower alkanol, for example a lower alkyl halide or sulfonate, in the presence of a basic condensing agent such as a hydroxide or carbonate of an alkali or alkaline earth metal or a heteroaromatic nitrogen base, for example pyridine.
• amino can be converted into lower alkanoylamino by treatment with the reactive functional derivative of a lower alkane carboxylic acid, for example the corresponding carboxylic acid halide.
• Salts of compounds of the formula I with salt-forming groups can be prepared in a manner known per se.
• salts of compounds of formula I with a free carboxyl or sulfo group e.g. by treatment with metal compound such as alkali metal salts of suitable organic carboxylic acid e.g. the sodium salt of ⁇ -ethyl caproic acid, or with inorganic alkali or alkaline earth metal salts, e.g. Form sodium bicarbonate, or with ammonia or with a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent.
• Acid addition salts of compounds of formula I are obtained in a conventional manner, e.g.
• Internal salts of compounds of formula I can e.g. by neutralizing salts such as acid addition salts to the isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.
• Salts can be converted into the free compounds in a conventional manner, metal and ammonium salts e.g. by treatment with suitable acids and acid addition salts e.g. by treating with a suitable basic agent.
• the process also includes those embodiments according to which compounds obtained as intermediates are used as starting materials and the remaining process steps are carried out with them, or the process is terminated at any stage.
• starting materials in the form of derivatives can be used or prepared in situ, if appropriate under the reaction conditions.
• nucleophilic reaction e.g. Lower alkanoyloxy such as acetyloxy or sulfonyloxy R0-SO2-, where R worin e.g. lower alkyl optionally substituted by hydroxy, such as methyl, tert-butyl or 2-hydroxyethyl, are known or can be known, for example, from published European
• the substitution can be carried out in an organic solvent, such as in a lower alkanol, a lower alkanecarboxamide, a cyclic ether, or in a similar inert solvent at room temperature or at a slightly elevated or reduced temperature, for example at about 0 ° to about 40 ° C.
• triphenylmethylthio or lower alkanoylthio radical W ⁇ is carried out in an analogous manner by reaction with an alkali metal salt, for example the sodium salt, a thioneower alkane carboxylic acid, for example thioacetic acid, or triphenylmethyl mercaptan.
• an alkali metal salt for example the sodium salt
• a thioneower alkane carboxylic acid for example thioacetic acid
• triphenylmethyl mercaptan triphenylmethyl mercaptan
• an acid-binding agent such as a tertiary alipha table amine, an aromatic amine, or in particular an alkali metal or alkaline earth metal carbonate or bicarbonate.
• an inert solvent such as a chlorinated hydrocarbon or an ether Room temperature or with heating or cooling, for example in a temperature range from approx. -50 ° to approx. + 60 ° C, in particular at approx. -30 ° to approx. + 20 ° C.
• Compounds of formula VI wherein X0 is a reactive esterified hydroxy group, in particular halogen, for example chlorine or bromine, are prepared by using a compound of formula V with a glyoxylic acid compound of formula R2 ⁇ -CHO or a suitable derivative thereof, such as a hydrate, hemihydrate or hemiacetal, for example a hemiacetal, with a lower alkanol, for example methanol or ethanol, and in a compound of the formula VI in which X0 is hydroxy, the hydroxyl group is converted into a reactive esterified hydroxyl group .
• the compounds of formula VI are usually a mixture of the two isomers [with respect to the grouping -CH (R ⁇ 2) X0] received.
• the addition of the glyoxylic acid ester compound to the nitrogen atom of the lactam ring in the compound of formula V takes place at room temperature or, if necessary, with heating.
• the hydrate of the glyoxylic acid compound is used, water is formed which, if necessary, is obtained by distillation, e.g. is removed azeotropically, or by using a suitable dehydrating agent.
• the process is preferably carried out in the presence of a suitable inert solvent or solvent mixture.
• the conversion of a hydroxy group X0 into a reactive esterified hydroxy group X0 in a compound of formula VI is carried out by treatment with a suitable esterifying agent, e.g. with a thionyl halide, e.g. -chloride, preferably in the presence of a basic, primarily organic basic agent, such as an aliphatic tertiary amine, or a heterocyclic base of the pyridine type. It is preferred to work in the presence of a suitable solvent, e.g. Dioxane or tetrahydrofuran, or a mixture of solvents, if necessary with cooling, e.g. at about -30 ° to about 30 ° C.
• a suitable esterifying agent e.g. with a thionyl halide, e.g. -chloride
• a basic, primarily organic basic agent such as an aliphatic tertiary amine, or a heterocyclic base of
• a suitable phosphine compound such as a tri-lower al
• the reaction with the phosphine or phosphite compound is preferably carried out in a suitable inert solvent, such as a hydrocarbon or an ether, or in a solvent mixture.
• a suitable inert solvent such as a hydrocarbon or an ether, or in a solvent mixture.
• the reaction is carried out under cooling or at an elevated temperature, for example between -10 ° and + 100 ° C, preferably at about 20 ° to 80 ° C.
• a basic agent such as an organic base, for example an amine, or "polystyrene Hunig base", or an inorganic base, for example an alkali metal carbonate
• the primary phosphonium compound of the formula in which X ⁇ is a phosphono group or a phosphonio group together with an anion, depending on the meaning of the radical X0 (see formula VI), for example chloride is converted into the ylide starting material of the formula II.
• the process described in Reaction Scheme 1 for the preparation of the compounds of the formulas (II), (III), (V) and (VI), and the stated processes for the preparation of the end products of the formula (I) can also be carried out using optically inactive compounds and isolate the optically active compounds according to the present invention in a known manner from any obtained diastereomer mixture or racemate at any process stage.
• the pharmacologically useful compounds of the present invention can e.g. be used for the production of pharmaceutical preparations which contain a therapeutically effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients which are suitable for oral or parenteral, i.e. e.g. intramuscular, subcutaneous or intraperitoneal, administration are suitable.
• tablets or gelatin capsules which contain the active ingredient together with diluents, e.g. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Tablets also contain binders, e.g.
• disintegrants e.g. Starches, agar, alginic acid or salts thereof, such as sodium alginate, and / or effervescent mixtures or adsorbents, colors, flavors or sweeteners.
• Infusion solutions are preferred for parenteral administration, preferably isotonic aqueous solutions or suspensions, these being, for example, from lyophilized preparations, which contain the active substance alone or together with a carrier material, for example mannitol, can be prepared before use.
• lyophilized preparations which contain the active substance alone or together with a carrier material, for example mannitol, can be prepared before use.
• Such preparations can be sterilized and / or contain auxiliaries, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers.
• the present pharmaceutical preparations which, if desired, may contain other pharmacologically valuable substances, are used in a manner known per se, e.g. by means of conventional mixing, solution or lyophilization processes, and contain from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilisates up to 100% of the active ingredient.
• daily doses oral or parenteral
• about 100 mg to about 2 g are used to treat warm flowers (humans and animals) weighing about 70 kg.
• the starting material can be produced as follows:
• a suspension of 1.84 g of 6- (tetrazol-1-yl) hexanoic acid in 40 ml of absolute methylene chloride is mixed with 1.52 ml of 1-dimethylamino-1-chloro-2-methyl-propene at room temperature and for 2 hours Room temperature stirred.
• the starting material can be produced as follows:
• the starting material can be produced as follows:
• Example 8 (5R, 6S) -2- [10- (tetrazol-1-yl) dec-1-yl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, sodium salt
• the starting material can be produced as follows:
• Example 13 (5R, 6S) -2- [3- (tetrazol-1-yl) prop-1-yl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid-1 -ethoxycarbonyloxyethyl ester
• the methylene chloride solution is concentrated to 2 ml and at 0 ° to a solution of 0.347 g (1 mmol) (5R, 6S) -2- [3- (tetrazol-1-yl) -prop-1-yl] -6- [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid in 4 ml of dimethylacetamide.
• the mixture is then stirred at 0 ° for 3 hours, then diluted with ethyl acetate and washed three times with water.
• the organic phases are dried over sodium sulfate and concentrated on a rotary evaporator.
• composition for 1 ampoule or vial:
• a sterile aqueous solution of the active substance and the mannitol is subjected to freeze-drying under aseptic conditions in 5 ml ampoules or 5 ml vials, and the ampoules or vials are sealed and checked.

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• 1988
  • 1988-01-08 EP EP88810006A patent/EP0275233A1/fr not_active Withdrawn
  • 1988-01-12 PT PT86534A patent/PT86534B/pt not_active IP Right Cessation
  • 1988-01-13 ZA ZA88212A patent/ZA88212B/xx unknown
  • 1988-01-13 AU AU10236/88A patent/AU1023688A/en not_active Abandoned
  • 1988-01-13 JP JP63003912A patent/JPS63174989A/ja active Pending
  • 1988-01-13 DK DK013588A patent/DK13588A/da not_active Application Discontinuation

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